2, 5-diazabicyclo-[2,2,1]heptanes and [2,2,2]octanes



United States Patent Office 3,167,561 Patented Jan. 26, 1965 Thisinvention relates to new heterocyclic bicyclic compounds. Morespecifically, this invention relates to 2,5-diazabicyclo-[2,2,1]heptanes and 2,5-diazabicyclo-[2,2, 2] octanes withor without substituents on the nitrogensi More specifically also, thisinvention relates to a compound of the formula CHIP-CH R1-N R N-R2err-on,

in which R and R are organic radicals and R is an alkylene bridge orless than 3 carbons. More specifically also, this invention relates to acompound of the formula CHrCH in which R and R may be hydrogen, alkyl,aryl, substiltuted aryl, heteroaryl, substituted heteroaryl, aralkyl,substituted aralkyl, substituted alkyl, alkanoyl, substituted alkanoyl,aroyl, heteroaroyl, aralkanoyl, aralken- FLOW SHEET A oyl, carboalkoxy,carbophenoxy, substituted carbophenoxy, acrbobenzyloxy,dialkylcarbamoyl, diarylcarbanoyl, carbalkoxyalkyl, arylsulfonyl,arylthio, nitroso, amino, aroylamino, alkylated amino, aralkylamino,heteroarylalkyl, N-heteroarylsulfonyl, N-heteroarylcanboxy and N-heteroarylaminoalkyl; and R is an alkylene bridge of less than 3 carbonsand to processes for the preparation of these compounds. Morespecifically also, this invention relates to bicyclic amides usable toprepare the above compounds.

We have found a new class of bicyclic heterocyclic compounds possessinga variety of utilities depending on the substituent on the nitrogenatoms. We have found unsubstituted bicyclic heterocyclic compounds whichare intermediates for other compounds of the class and which also haveutility in their own right in various biochemical activities. TheN-substituted compounds of this invention as well as the un-substitutedcompounds may be antihistaminics, antiemetics, antiallergics,tranquilizers, antiparisitics, hypotensives, central nervous systemdepressants, sedatives, antibiotics, antispasmodics, analgesics, and insome cases central nervous system stimulants and the like. For example,2[u-(2-chloro-10-phenothiazinyl)propy1] 5 hydroxyethyl-Z,S-diazabicyclo-[2,2,2]octane shows strong activity as a tranquilizer while theunsubstituted 2,5-diazabicyclo-[2,2,2] octane is active as ananthelrnintic as well as usable as an intermediate for the preparationof the N-substituted compounds, as shown in the flow sheet and examplesof these specifications. As an anthelmintic, this latter compound isused in a dose of at least 100 mg] kg. orally.

Br Br CH COOH (EH-COOK ATE-C001 Ra\ R3 R3 CH -COOH CH-COOH CH-COCI 1'" r(I) 11) (in) B1 ('JH-COORI (EH-000m Br (Iv) o o 7 I O-N NHRi NHRi(EH-000R; (EH-000R (EH-COOP vRa\ Ra Ra C'5H-COOR4 CH-COORt CH-COORA(fO-N l lHRi 1 31: (XV) l (XIII) (v) Q @l j FLOW SHEET A Continued l I!I! i/ M NH; (I) NHRi NHR; JH-COOR -CH lit-000R (EH-000124 Ra R1N R NR1Ra Ra (EH-000R CH-|) CH-COOR! OH-COOR4 NH, O NH: NHR:

(VI) (XIV) (XVI) (XVIII) l i l e i if i I 7 )5 H-N\ /R3 /NH R1-N\ /RaN-Ri R1-N\ /Ra NH R1N\ /Ra N-Rfl CHC CH-CH, CHC CHC I] ll H O O (VII)(IX) (XVII) (XIX) @7' l@ 1 F7"? 7 5 2 7 5 H-N\ /R3 /N-H R1-N\ /R3 /NH'--P R1N\ Ra /NR1 OH, (DH-CH CH--OH,

(VIII) (X) I (XI) /CHa/CH HN\' /Ra N-Ra CH-CH1 (XII) FLOW SHEET B FLOWSHEET B-Continued 000m 000m CIOORA I I l a-(BE Put-(113i Br s H N-CH/Nl-I m-NH-( JH /NR1 R1 NH-E /NR: 40 COOR 000R 0H, CH CH 5 RFCH (XX)(XXII) (XXIV) RI NH'- H NH HZN CH N-Rl CH1 CH2 (XXVI) (XXVIII) O O OEquivalents: I IL R1 and R2 are as defined in the specifications, exceptthat they are used to indicate groups other than hydrogen R and tligt1the group; are difierent. ssme yeneore yene H N N H N R3 N N R3 N R4islanlyi elstelrifying iglfoup (alllkyl aryl, amfilkyll, alkenygl, O eye0a 'y owe]: a oxymet y, cyanome y, or su H H OH stituted derivativesthereof) preferably lower alkyl such (XXI) (XXIII) (XXV) as methyl orethyl.

Reagents:

(D Br: and UV light. (3 E3? $9 11 tf t R OH cru e ro uc ram 0 /CE /CECHz-CE CHr/ E 1 inidi iiert solvent (e.g., DMF) with potassium p a 1m e.H-N R3 NH ,R1N Ra -Rx R1-N Ra NR2 v@ Heat with organic or inorganic base(e.g., hydrazine hydrate) in inert solvent (e.g., RIOH).

H-CHa H-CH: H- Hz Heat in inert solvent (e.g., CHaOH) containing atleast (VIII) (IX) (XI) catalytic amount of strong base (e.g., NaOCHs).

Heat with strong reducing agent for carbonyls (e.g., LiAlI-h) in inertsolvent (e.g. dioxane).

7 Reaction with 2 or more moles of R1X where X is group N g easily splitoff in reaction with amino group, usually OH CH XII halogen but alsosulfonate, epoxide, dlazides, etc.). F/ Reaction can be run in aqueousalkaline suspension of RFN R3 1(VIIDtorlorgtttnic basecontainingrsolution of (VIII) I n ner so ven H CH Reaction with 1 moleof RIX in same manner as (D, but

1 usually controlled by following pH and tltrating. (X) Reaction withRzX in same manner as 7 R Removal of certain R1 groups by special meansnot aifectng tliig Rt; gr)oup (e.g., where R1 is acyl and R2 alkyl,

apon ca 1011 o 0 525E311: of with R1X where R1 is diiferent from origi-1- 4]; l l Reaction with excess RiNHz in a high boiling solvent 7 3 i'tattifi iri nti l t i "f if t g e. 2 a usn ressurew en R1-N Ra NH H-N Rs-R1 7O needed to retain the am ine in the mixt u 'e at the elevatedtemperature used (150 C. or higher). 11- 2 H-CH: geiictiogbwith 1 nole0g RiNltiz in same manner as 0 owe y separa ion 0 roma ographica 1y,usin ether- (XXVH) (XXIX) peltroleum ether mixtures to elute from anzflumina c0 umn. I I Reaction with ReNI-Iz in same manner as Reactionwith NHa in same manner as using pressure.

The compounds of this invention are prepared by a number of routes asdescribed in the flow sheet. The most important routes are those shownin Part A of the fiow sheet. As can be seen, these depend primarily onthe formation or" a,ot-dibromodibasic carboxylic esters of the generalformula shown by Compound 1V. These are prepared by taking a dibasicacid and brominating the ct-carbons and converting the carboxyls throughthe acid chlorides to ester groups. The bromination is carried out in aninert solvent such as carbon tetrachloride in the presence of a redphosphorous catalyst. The acids used as starting materials are glutaricand adipic acids. After bromination the carboxyls are esterified byreaction with thionyl chloride to form the acid chloride and reaction ofthe latter with an alcohol to form the ester. This bromo ester is theintermediate from which we have divers synthetic routes start, dependingon What compounds are desired. In the most fiexible of these, thebromine is replaced by the amino either through the phthalimide ordirectly with ammonia. The phthalimide reaction is carried out byheating in an inert solvent such as dimethylfcrmamide (hereinafterabbreviated DMF), with potassium phthalimide. The bisphthala imido esteris readily converted by heating with a base such as hydrazine hydrate tothe diamino ester. Alternatively, the dibromo ester can be heated underpressure with ammonia, a copper catalyst, in a high-boiling solvent suchas nitrobenzene containing an acid-binding agent such as sodiumcarbonate directly into the diamino ester. The a,a' diamino-diester(Compound VI) is then cyclized to a cyclic bisamide by heating in aninert solvent such as methanol in the presence of at least a catalyticamount of an anhydrous base such as sodium methoxide. The cyclicbisamides (VII) thus produced form one embodiment of this inventionusable as an intermediate for preparation of the latter compounds.

The amide carbonyls of the bisamides are reduced by treatment with anystrong carbonyl reducing agent such as lithium aluminum hydride in aninert solvent such as dioxane. The resulting diazabicyclo heptane oroctane (VIII) is the simple unsubstituted compound of this invention.substituents on the nitrogen can be introduced in a variety of ways. Asymmetrical bis-substituent can be carried out by heating either inaqueous solution or in an organic inert solvent in the presence of anorganic base with a reagent readily reacting with an amino nitrogen suchas an alkylating agent, an acylating agent and the like. Usually suchreactions are carried out by the elimination of a hydrogen halide toform the new bond to the nitrogen, e.g., heating with an excess of analkyl halide or an acyl halide. However, other special reagents may beused to introduce groups ditficult to introduce by the simpler method.Thus, e.g., the method of Beringer described in the Journal of theAmerican Chemistry Society, 75, 2708 (1953) can be used to introducearyl groups onto the nitrogens. This method involves the reaction of adiaryl iodonium bromide with a secondary amine. The method of Sus et al.in Annalen, 598, 123 (1956) also can be used. In general, the methods ofintroducing the various substituents on the nitrogen are illustrated inthe examples and depend to a large extent on the type of substituentwhich is to be introduced.

Alternatively, one can introduce substituents directly from the dibromoester as shown in the flow sheet by reaction with the proper amine oramide in a high-boiling solvent such as nitrobenzene and in the presenceof a copper catalyst and an acid-binding agent such as sodium carbonate.This method, although somewhat less general than the other route, ismore direct in the case of some substituents and in the case of thosesubstituents which are difficult to introduce later, may well be theonly Way to reach the final product. This introduction of an aminonitrogen into the diester may need the use of pressure when the amineboils too low for the temperature necessary for the reaction, at 150 C.or higher.

I nitrogen.

The use of an excess of amine to be introduced will give the symmetricaldi-substituted amino ester, which upon ring closure, gives asymmetrically N-substituted bicyclic amide. Reduction of the amidecarbonyls as before yields the symmetrically substituteddiazabicycloheptane or octane. When the usage of the amine in thereaction with the bromo-ester is approximately mole for mole, a mixtureof di-substituted and mono-substituted amino ester is obtained, whichcan be separated chromatographically. The a-substituted amino-a'-bromodiester (XV) can then be reacted either with ammonia or with potassiumphthalimide to replace the bromine with an unsubstituted amino group.

Alternatively, reaction with another mole of a dilierent amine willreplace the bromo with a difierent substituted amino group. Ring closureof either of these gives the correspondingly substituted bicyclic amidewhich can then be reduced as before to the diazabicyclo heptane oroctane having only one nitrogen bearing a substituent, or having twonitrogens bearing different substituents.

These latter compounds are also preparable directly from theunsubstituted diazabicyclo heptane or octane by the sequence shown inthe flow sheet in reactions and Mono substitution is achieved byreaction of one mole of the reagent with the unsubstituted diazabicycloalkane while following the reaction with a pH indicator since thebasicity of the amino nitrogen is changed by substitution. Usually, thisis done by an acylating reagent to introduce an acyl group. A furthersubstituent can then be introduced as shown by reaction in the flowsheet and the acyl group can be removed as shown in reaction to getanother mono substituted compound which otherwise might be much moredifiicult to obtain.

The acrylation of the diazabicyclo compound with an acyl halide isreadily followed with a pH meter and the eiiect is to block one nitrogenand permit easy substitution by any desired reagent or substitutinggroup on the other The acyl group can then be removed to get a desiredmono substituted compound and if desired a second and differingsubstituent can then be put on the unblocked nitrogen as shown inreaction 6).

An alternative method of preparing these compounds is shown in Part B ofthe flow sheet. This method starts with a heterocyclic amino 'carboxylicester with or without substituents on the nitrogens. Various of thesecompounds are readily available in the literature and where they areavailable they form a simple and easy way to get to the compounds ofthis invention. These amino heterocyclic esters illustrated by thecompounds of Formulae XX, XXII, XXIV, XXVI, and XXVIII in the flow sheetall are ring closed by the same procedure used before for the bisamideinto a bicyclic mono amide having another hetero atom and this can thenbe reduced to form the desired diazabicyclo heptane or octane.

The substituents R and R which can thus be put upon the nitrogen can benitroso, amino or substituted amino, or any organic radical which isnormally linkable to a basic nitrogen. Thus, e.g., it may, in additionto hydrogen and the nitroso and amino groups, be acyl, such as benzoyl,acetyl, chloracetyl, dichloroacetyl, propionyl, cinnamoyl, thenoyl,furoyl, nitrofuroyl, nicotinoyl, pyrazinoyl, thiazolecarbonyl,phenylacetyl and the like. Also, it may be carboalkoxy, carbophenoxy,carbonitrophenoxy, carboethoxy, carbobenzyloxy and the like. It may alsobe alkyl such as ethyl, methyl, propyl, butyl, cyclohexyl and the likeor substituted alkyl such as [imp-trifluoroethyl, carbethoxyethyl,cyanoethyl, hydroxyethyl, phenethyl, aminoethyl, acetylaminoethyl,dimethylaminoethyl or N-chlorophenothiazenyl propyl. It may be an arylgroup such as phenyl, tolyl or a substituted aryl group such ashydroxyphenyl, aminophenyl, acetylaminophenyl, dimethylaminophenyl andthe like. It may also be an aralkyl group such as a benzyl, phenethyl,phenylethylmethyl and the like or aralkenyl such as cinnamyl. It mayalso be a heterocyclic aroyl such as N-morpholinylsulfonyl,N-pyrrolidinylsulfonyl and the corresponding carboxy compounds and thelike. It may also be an arylthio such as tolylthio, phenylthio orarylthioalkyl such as benzylthiomethyl. Thus, it can be seen that thereis a wide range of substituents which may be placed on the nitrogen inthe compounds of our invention.

Our invention can be illustrated by the following examples: 1

EXAMPLE 1 Dimethyl a,u'-dibr0m0 adipate A mixture of 500 g. of adipicacid and 1 kg. of thionyl chloride is heated overnight on a steam bath.The excess thionyl chloride is then removed by distillation underreduced pressure. The diacid chloride is then heated on a steam bathwith stirring and 402 ml. (1.25 kg.) of bromine is added dropwise at arate such that no bromine is lost to the condenser. A photoflood lamp isused to accelerate the reaction. After complete addition of the bromine,the reaction mixture is heated overnight on a steam bath. It is thenadded in a thin stream to 690 ml. of methanol, with stirring. Themixture is cooled in an ice bath and if necessary seeded. The crystalsare obtained by cooling an aliquot in dry ice. The crystallized materialis filtered and washed with cold methanol. After several weeks, moreproductcrystallizes from the filtrate and this also is filtered andwashed with cold methanol. It can be recrystallized from boilingmethanol. The product melts at 74-76 C.

EXAMPLE 2 Dimethyl a,et'-diphthalimid0 adz'patc A mixture of 69 g. ofdimethyl-a,u-dibromoadipate (prepared in Example 1), 87 g. of potassiumphthalimide and 260 ml. of dimethylformamide is heated on a steam bathto about 90 C. with occasional agitation for about an hour. The mixtureis then allowed to cool and is diluted with 300 ml. chloroform. It isthen poured into 1200 ml. of water and the chloroform layer separated.The aqueous layer is extracted twice with 100 m1, chloroform and thecombined extracts are washed with 200 ml. of cold 0.1 N sodium hydroxidesolution, followed by 200 ml. Water and then dried over sodium sulfate.The chloroform is removed under reduced pressure to the point ofcrystallization. Three hundred (300 ml.) of ether is then added and themixture is agitated. Rapid crystallization occurs and the mixture isallowed to stand until the process is complete. It is then filtered andthe product is washed with ether and air dried. A yield of 87.3 g. (91%)of bisphthalimido adipic acid dimethyl ester is obtained; M.P. 162-190.Upon recrystallization from boiling ethyl acetate, this product meltedat 197- 204.

A second crop of product is obtained by concentrating in vacuo to thepoint of crystallization. Further crops can similarly be obtained byfurther concentration of the filtrate.

EXAMPLE 3 a,ot-Diamin0adipic acid and dimethyl m,a-diamiu0adipatc A. Amixture of 52.5 g. of dimethyl-a,ot'-diphthalimido adipate, 565 ml. ofmethanol and 13.5 ml. of 85% aqueous hydrazine hydrate solution isrefluxed for one hour. The mixture is then cooled and 283 ml. of Wateris added. The methanol is then removed in vacuo and the residual aqueoussuspension is treated with 283 ml. concentrated hydrochloric acid andrefluxed for one hour. The reaction mixture is then cooled overnight.The crystallized phthalhydrazide is removed by filtration and thefiltrate concentrated in vacuo to remove the hydrochloric acid. Theresidue is dissolved in 565 ml. of Water. The solution is filtered andneutralized with 2N sodium hydroxide. The mixture is then cooled in arefrigerator and the crystallized product is isolated by filtration,

washed with cold water and air dried to yield 12.5 g.

(63%) of a,a-diarnino adipic acid. Melting point, with decomposition,303 C.

B. A mixture of 10.5 gms. of a,o'-dia1ninoadipic acid in 500 ml. ofmethanol is saturated with anhydrous hydrogen chloride and refluxedovernight. The solution is concentrated in vacuo to a small volume andexcess ether is added. The mixture is allowed to stand at roomtemperature overnight. The white precipitate is filtered, washed withether and dried in vacuo to yield 16.9 gms. of dimethyla,a-diarninoadipate dihydrochloride. Melting point, with decomposition201203 C.

EXAMPLE 4 2,5 -diaza-3,6-dioxobicycl0- [2,2,2 octane 10 g. of dimethyla,a-diamino adipate dihydrochloride is suspended in 1000 ml. of methanoland 3.9 g. of sodium methoxide is added. The mixture is refluxed for 8hours and then allowed to stand at room temperature for several days.The solvent is evaporated under reduced pressure and the residual whiteproduct is extracted with excess boiling chloroform in a continuousextraction. The chloroform extract is then evaporated to dryness. Theresidue is recrystallized from boiling methanol. The

product sublimes and melts at 727-273 C. Analyis.-- Calcd. for C H N OC, 51.42; H, 5.75; N, 19.99. Found: C, 51.22; H, 5.99; N, 220.13. 7

EXAMPLE 5 2,5-diazabicyclo- [2,2,2]octane A mixture of 5, g. of theproduct of Example 4, 2 g. of lithium aluminum hydride and 50 g. of drydioxane is stirred and refluxed for 46 hours. The mixture is then cooledand excess ethyl acetate is added. The insoluble material is filteredand washed with excess boiling ethyl acetate. dryness at atmosphericpressure. The residual product is the desired diazabicyclo octanecontaining some impurities. It is usable directly for acylation.

The crude product is distilled in vacuo and the portion boiling at 91 C.at 15 mm. is collected in a flask immersed in a Dry Ice bath. Thisdistillate is dissolved in dry ether and treated with dry hydrogenchloride. The white precipitate is filtered, washed with ether anddissolved in boiling methanol. The methanol solution is concentrated invacuo to the start of crystallization, diluted with excess ethyl acetateand cooled. The crystalline dihydrochloride is filtered, washed withether and dried in vacuo. It gradually decomposes Without melting uponheating at 335 C. Calcd. for C H CI N C, 38.93; H, 7.62; N, 15.14; Cl,38.31. Found: C, 38.96; H, 7.50; N, 15.15; Cl, 37.89 (total), 38.03(ionic).

EXAMPLE 6 2,5-diazabicyclo-[2,2,1]heptane The procedure of Example 1 isfollowed using an equivalent quantity of glutaric acid and the resultantproducts are carried through the procedures of Examples 2, 3, 4, and 5to produce 2,5-diazabicyclo-[2,2,1] heptane and its dihydrochloride.

EXAMPLE 7 2,5 -dibcnz0yl-2,5 -diazabicycl0- [2,2,2] octane A. Two partsof 2,5-diazabicyclo-[2,2,2]octane dihydrochloride and 25 parts 10%sodium hydroxide solution are stirred and cooled while 6 parts benzoylchloride is slowly added. The mixture is allowed to come to roomtemperature. The precipitated solid is filtered, washed with 2.5 Nhydrochloric acid, water, saturated sodium bicarbonate solution, waterand then dried. Recrystalliza tion from benzene-Skellysolve B gives the2,5-dibenzoyl- 2,5-diazabicyclo-[2,2,2]octane melting at 181-183".

B. A mixture of two parts of 2,5-diazabicyclo-[2,2,2] octane in 25 partsdried pyridine is cooled and stirred while 6 parts benzoyl chloride isslowly added dropwise. The

The filtrates are combined and evaporated to mixture is allowed to stirin cold about 1 hour and then at room temperature overnight. Thereaction mixture is poured into excess water with stirring and in ashort while a solid forms. The solid is filtered and washed with cold2.5 N HCl, water, saturated sodium bicarbonate and finally with water.After air drying and recrystallization from benzene-Skellysolve B the2,5-dibenzoyl-2,5-diazabicyclo-[2,2,2] octane is obtained.

Similarly, when acetyl chloride, dichloroacetyl chloride,,B-bromopropionyl chloride, cinnamoyl chloride, phenylchloroformate,p-nitrophenylchloroformate, ethylchloroformate, diethylaminocarbonylchloride, diphenylaminocarbonyl chloride, 2-thenoyl chloride, 2-furoylchloride, 5-nitro-2-furoyl chloride, nicotinoyl chloride, pyrazinoylchloride, 4-thiazolcarbonyl chloride, phenylacetylchloride,a-ethylphenylacetyl chloride, B-naphthoyl chloride,3,4,5-trimethoxybenzoyl chloride, 2-rnethoxybenzoyl chloride, andacetylsalicyloyl chloride are substituted in equivalent quantities forthe benzoyl chloride in the above procedures, there are obtained:

2,5-diacetyl-2,4-diazabicyclo-[2,2,2] octane,

2,5-bis(dichloroacetyl)-2,5-diazabicyclo-[2,2,2]octane,

2,5 -bis 6 bromopropionyl) 2,5 diazabicyclo [2,2,2]

octane,

2,5 -dicinn amoy-2,5-diazabicyclo- [2,2,2 octane,

Diphenyl-2,S-diazabicyclo-[2,2,2]octane-2,5 dicarboxylate,

Bis(p-nitrophenyl)-2,5 diazabicyclo [2,2,2] octane 2,5-

dicarboxylate,

Diethy1-2,S-diazabicyclo-[2,2,2]octane-2,S-dicarboxylate,

2,5-bis(diethylcarbamoyl)-2,5-diazabicyclo-[2,2,2]

octane,

2,5-bis(diphenylcarbamoyl)-2,5-diazabicyclo-[2,2,2]

octane,

2,5 -bis 2-thenoyl -2,5 -diazabicyclo- [2,2,2] octane,

2,5-bis(2-furoyl)-2,5-diazabicyclo-[2,2,2]octane,

2,5 -bis 5 -nitro-2-furoyl -2,5 -diazabicyclo- 2,2,2] octane,

2,5-dinicotinoyl-2,5-diazabicyclo-[2,2,2]octane,

2,5 -dipyrazinoyl-2,5 -diazabicyclo- [2,2,2] octane,

2,5-bis(4-thiazole carbonyl)-2,5-diazabicyclo-[2,2,2]

octane,

2,5 -bis phenylacetyl -2,5 -diazabicyclo- [2,2,2] octane,

2,5-bis(a-ethyl-phenylacetyl)-2,5-diazabicyclo-[2,2,2]

octane,

2,5 -bis B-naphthoyl 2,5-bis(3,4,5-trimethoxybenzoyl)- 2,5-bis(acetylsalicyloyl)- 2,5-bis(o-methoxybenzoyl)- EXAMPLE 8Z-benzoyl-2,5-diazabicycl0-[2,2,2]octane Four and eight-tenth grams of2,5-diaZabicyclo-[2,2,2] octane dihydrochloride is dissolved in 48 ml.water. Using a pH meter, with stirring, 2.5 N hydrochloric acid is addeddropwise to bring the pH to 3, after which 48 ml. of acetone is added.Three ml. of benzoyl chloride is then added a few drops at a time. Asthe pH starts to drop towards 2.5, a solution or" sodium acetate (40gms./ 100 ml. water) is added to bring the pH of the mixture back to 3.The next batch of benzoyl chloride is not added until the pH remainsconstant. During the entire addition, the pH is kept 3.1-2.5. Aftercomplete addition, stirring is continued at pH of 3. The small amount ofprecipitate, which is the dibenzoyl derivative, is filtered. Thefiltrate is saturated with potassium carbonate and extracted with excesschloroform. The chloroform extract is dried and evaporated to dryness.The residue is triturated with ether and the slurry is filtered to give35 gms. of crystalline 2-benzoyl-2,S-diazabicyclo- [2,2,2]oct ane,melting at l09-1l1 C..

When the various acid chlorides used in Example 7 are used in place ofthe benzoyl chloride in the above procedure, the correspondingmono-acyldiazabicyclo octane is obtained.

1% EXAMPLE 9 Dibenzyl 2,5 diazabicyclo [2,2,2]0Clane 2,5 dicarbOxylateand benzyl-2,5-ditzzabicyclo [2,2,2]0ctane-2- carboxylate The procedureof Example 7 is followed using carbobenzyloxy chloride in equivalentquantities in place of benzoyl chloride to producedibenzyl-Z,S-diazabieyclo- [2,2,2]octane-2,5-dicarboxylate.

The procedure of Example 8 is followed similarly using carbobenzyloxychloride in equivalent quantities in place of benzoyl chloride toproduce benzyl-2,5-diazabicyclo- [2,2,2] octane-Z-carboxylate.

EXAMPLE 10 2,5 -dimethyl-2,5 -diazabicycl0- [2,2,2]oczane One mole of2,5-diazabicyclo-[2,2,2]octane and two moles of methyl iodide in 40parts methanol are heated for one hour on the steam bath under anefiicient condenser. A precipitate of 2,5-dimethyl-2,S-diazabicyclo-[2,2,2]octane dihydroiodide soon precipitates. The reaction mixture iscooled and filtere and the precipitate is washed with cold methanol. Thesalt is dissolved in a minimum amount of water, saturated with potassiumcarbonate and extracted with excess chloroform. The chloro form extractis dried and evaporated to dryness to yield the crude product, which isdistilled in vacuo to give a pure product.

EXAMPLE 11 2,5 -di phenyl-2,5 -diazabicycl0- [2,2,2 Octane The procedureof Hager, Org. Syntheses, Coll. vol. 1, page 544 (1942) is followedusing 2,5-diazaoicyc1o- [2,2,2]octane in half the equivalent quantityfor the diphenylamine. The produce thus obtained is 2,5-diphenyl-2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 12 2,5 -bis-p-hydr0xyphenyl-2,5-diazabicycl0-[2,2,2]0ctaneOne-tenth of a mole of 2,5-diazabicyclo-[2,2,2]octane is dissolved in300 cc. of dimethylformamide and twotenths mole (24 g.) of1,4-benzoquinone diazide is added. The mixture is irradiated by anultraviolet lamp in the manner as described by O. Sus et al. in Ann.598, 123-38 6), until the reaction is substantially complete. Thesolvent is removed under reduced pressure and the residue ischromatographed on 900 g. of silica gel using a mixture of ether-ethylacetate as eluent to yield2,5-bis-p-hydroxyphenyl-Z,S-diazabicyclo-[2,2,2]octane.

When an equivalent quantity of acetamino quinone diazide, substituted inthe above procedure for 1,4-benzoquinone diazide, there is obtained2,5-bis(p-acetaminophenyl)-2,5-diazabicyclo-[2,2,2]octane. This productis heated with 5 N sodium hydroxide in 50% aqueous ethanol at refluxuntil hydrolysis is complete. The mixture is concentrated in vacuo toone half volume, saturated with potassium carbonate and then extractedwith ether. Evaporation of the ether solution gives2,5-bis(paminophenyl)-2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 13 2,5-bis(p-dimethylaminophenyl)-2,5-diazabicycl0 [2,2,2]octaneUsing the reductive alkylation procedure of Woodruff et al., J.A.C.S.62, 924 (1940) the treatment of 0.1 mole of2,5-bis(p-aminophenyl)-2,5-diazabicyclo-[2,2,2]octane and 0.3 mole offormaldehyde gives the2,5-(p-dimethylamiuophenyl)-2,5-diazabicyclo-[2,2,2]octane afterfractionation of the residual oil.

EXAMPLE 14 2,5 -bis-benzyl-2,5 -diazabicycl0- [2,2,2 octane A. One partof 2,S-dibenzoyl-Z,S-diazabicyclo-[2,2,2] octane, suspended in 25 .partsfreshly distilled dry tetrahydrofuran, is added slowly to a stirredsuspension of T l 1 part lithium aluminum hydride in 100 parts oftetrahydrofuran. After addition is complete, the mixture is refluxedovernight. It is then cooled in ice and 5 parts Water is added dropwisewith stirring. The mixture is allowed to come to room temperature over 2hours and filtered. The solids are washed with ether. The Washings arecombined with original filtrate and the whole is taken to dryness invacuo. The residue is dissolved in a minimum amount of methanol. withdry hydrogen chloride and diluted with excess dry ether. The white solidwhich precipitates is filtered, after it has been allowed to standovernight. The precipitate is washed with ether and dried in vacuo atroom temperature. The di hydrochloride of the product solvates with 1mole of water, melting slowly to 175 C.

B. The identical product is obtained by adding 2 moles of benzylchloride to 1 mole 2,5-diazabicyclo[2,2,2]octane in 500 parts ethanoland allowing the mixture to stand at room temperature for several days.Evaporation of the reaction mixture gives a crude solid which isdissolved in a minimum amount of water, saturated with potassiumcarbonate and extracted with excess chloroform. Evaporation of the driedchloroform and subsequent distillation of the residue gives the desiredproduct in a pure state.

EXAMPLE 15 2,5-bis-carbethxymethyl-2,5-diazabicycl0-[2,2,2]0czane V Theprocedure of Adelson and Pollard, J.A.C.S. 57, 128-0 (1935) is followedusing 2,5-diazabicyclo-[2,2,2] octane. The process consists of reactionwith ethyl chloracetate in ethanol in the presence of sodium carbonate.The product is purified by distillation in vacuo.

When the above procedure is followed, substituting an equivalentquantity of chloracetonitrile for the chloracetate, there is obtained2,5-bis-cyanomethyl-2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 16 2,5 -bz's-,8-cyan0etlzyl-2,5 -diazabicyclo [2,2,2 octane Awell-mixed solution of 0.3 mole of 2,5-diazabicyclo-' [2,2,2]octane and0.6 mole of acrylonitrile is warmed to 50. The mixture is then allowedto stand overnight, cooling to room temperature. The product is purifiedby distillation of the crude residue to obtain2,5-bis-[3-cyanoethyl-2,5-diazabicyclo- [2,2,2] octane.

EXAMPLE 17 2,5-bis-[3-hydroxyethyl-2,5-diazabicycl0- [2,2,2 octane Asolution of one part of 2, -diazabicyclo-[2,2,2]octane in 25 parts ofcold methanol is treated with an excess of ethyleneoxide. The mixture isthen allowed to stand in the cold for at least one day, followed by atleast another day at room temperature. The solvent is removed :bydistillation under reduced pressure and the crude residue is distilledin vacuo to yield 2,5-bis-[3-hydroxyethyl-Z,S-diazabicyclo-[2,2,2]octane.

EXAMPLE 18 2,5 -bis-/3-aminoethyl-2,5 -diazabicycl0- [2,2,2] octane Amixture of one part of the 2,5-bis-cyanomethyl-2,5-diazabicyclo-[2,2,2]octane produced in Example 14 and one part oflithium aluminum hydride in freshly distilled tetrahydrofuran is heatedgently overnight with agitation under an atmosphere of nitrogen. Eightparts of cold water and then three parts of 2.5 Nsodium hydroxidesolution are added, with stirring, .to the cooled reaction mixture.After about one hour the mixture is filtered and the solids washed withether. The filtrates are combined, dried over potassium carbonate, andevaporated to a liquid residue. The residue is chromatographed on 20parts of alumina using a mixture of ether-methanol as eluent.

The solution is saturated i2 EXAMPLE 19 2,5 -bis-B-acetylaminoethyl-Z ,5-d iazabicyclo- [2,2,2]0ctane- A solution of 0.0 1 mole of2,5-bis-(fl-aminome'thyD- 2,5-diazabicyclo-[2,2,2]octane in 25 ml. drypyridine is cooled-and stirred, while 0.02 mole of acetyl chloride isadded dropwise. After complete addition the stirred reaction mixture isallowed to come to room temperature overnight. The mixture is pouredinto an ice-water mixture with stirring. The precipitate is separatedand Washed with water. Skellysolve B gives a pure product.

EXAMPLE 20 2,5 -bis-dimethylaminoethyl-2,5-diazabicycl0- [2,2,2]

octane A mixture of 0.067 mole of 2,5-diazabicyclo-[2,2,2] octane, 0.14mole of fi-dimethylaminoethyl chloride and 26 g. of powdered potassiumhydroxide in ml. of acetone are refluxed with stirring for 2.5 hours.The reaction mixture is then filtered and the solid product is washedWith acetone. The filtrate is dried over potassium hydroxide, filtered,and then evaporated to dryness. The residue is purified by absorption onalkaline alumina and elution with mixtures of petroleum-ether and ether.

EXAMPLE 21 2,5 -bis-(1 ,4-benzodioxane-2-yl-methyl-2,5 -diazabicyclo-[2,2,2 octane A mixture of 56 g. of 2,5-diazabicyclo-[2,2,2]octane, g.of chloromethyl benzodioxane and 40 g. of sodium hydroxide in 125 ml. ofwater is refluxed for 96 hours and then cooled. The separated product iscollected and washed with water followed by methanol and dried. Theproduct can be recrystallized from a mixture of chloro form and methanolto give 2,5-bis-(1,4-benzodioxane-2-yl-methyl-Z,S-diazabicyclo[2,2,2]octane.

EXAMPLE 22 2,5-bis-p-a'imethylamin0benzenesulfonyl-Z,5-diazabicycle-[2,2,2]0ctane2,5-bis-p-tolylthio-2,5-diazabicyclo- [2,2,2]octane One adds to asolution of 11.8 g. of 2,5-diazabicyclo- [2,2,2]octane in 100 ml. ofabsolute ether, an ether solution of 15 g. of p-tolyl sulfenyl chloride,dropwise, with cooling. The separated hydrochloride of the excessdiazabicyclo octane is filtered and the filtrate is evaporated underreduced pressure. The crude product is recrystallized from hexane. It is2,S-bis-prtolylthio-2,5-diazabicyclo- [2,2,2] octane.

. EXAMPLE 24 2-benzoyl-5-lzydroxyethyl-2,5-diazabicyclo- [2,2,2]

' octane Five parts of 2-benzoyl-2,S-diazabicyclo-[2,2,2]octane isdissolved in 50 parts methanol and cooled. A solution of 5 partsethylene oxide in 50 parts cold methanol is added. The mixture isallowed to stand in an ice bath all day and then come to roomtemperature overnight. The solvent is removed on a steam bath atatmospheric Recrystallization from benzene-' pressure to give 6.4 partscrude product. Purification is achieved by chromatography on a silicagel column (300 parts) using a mixture of ether-ethyl acetate as eluent.

EXAMPLE 25 2 -hydrxyelhyl-2,5 -diazabicycl0- [2,2,2 octane A mixture of6.4 parts of2-benzoyl-5-(/B-hydroxyethyl)-2,5-diazabicyclo-[2,2,2]octane and 100parts 2.5 N sodium hydroxide solution is refluxed overnight. Thereaction mixture is then saturated with potassium carbonate andextracted with excess chloroform. The chloroform extract is dried andevaporated to dryness in vacuo to give 3.9 parts of2-hydroxyethyl-2,S-diazabicyclo- [2,2,2]octane.

EXAMPLE 26 2-benzoyl-5-me2hyl-2,5-diazabicycl0- [2,2,2]0ctane Theprocedure of Example 10 if followed using onehalf the quantity of methyliodide and an equivalent quantity of2-benzoyl-2,5-diazabicyclo-[2,2,2]octane in place of the reactants usedtherein. The product obtained is 2- benzoyl--methyl-2,S-diazabicyclo-[2,2,2] octane.

EXAMPLE 27 2 -m ethyl-2 ,5 -dz'azabicycl0- [2,2,2] octane The procedureof Example 25 is followed using an equivalent quantity of the product ofExample 26 in place of the 2-benzoyl-S-B-hydroxyethyl-diazabicyclooctane used in that example. There is thus obtained Z-methyl-2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 28 2- (N -m0rpholiny l-sztl fonyl -2,5 -diazabicycl0- [2,2,2]octane-5-benzyl carboxylate The procedure of Example 7 is followed usingas the reactants benzyl 2,5-diazabicyclo-[2,2,2]octane-2-carboxylateprepared in Example 9 and 4-morpholinyl sulfonylchloride. The productobtained is Z-(N-morpholinyl-sulfonyl) -2,5-diazabicyclo- 2,2,2]octane-5-benzy1 carboxylate.

When the same procedure is followed using l-pyrrolidinosulfonyl chloridein equivalent quantities, one obtainsbenzyl-2,5-diazabicyclo-[2,2,2]octane-5-(l-pyrrolidinosulfonyl)-2-carboxylate.

Also, using the same procedure, but substituting an equivalent quantityof 4-morpholinocarbonyl chloride and benzyl-2,5-diazabicyclo- 2,2,2octane-Z-carboxylate there is obtained thebenzyl-2,5-diazabicyclo-[2,2,2]octane-5- (4-morpholinocarbonyl-2-carboxylate.

Also, again using the same procedure, but substituting an equivalentquantity of l-piperidinocarbonyl chloride instead of4-morpholinocarbonyl chloride, there is obtained thebenzyl-2,5-diazabicyclo-[2,2,2]octane-S-(l-piperidinocarbonyl)-2-carboxylate.

EXAMPLE 29 2-(4-m0rpholin0sulf0nyl)-2,5-diazabicycl0- [2,2,2]0ctane Theproduct of Example 28 is hydrogenated in an alcoholic solution ofpalladium charcoal or over palladium on barium sulfate. The result isthe removal of the carbobenzyloxy group to form 2-(4-morpholinosulfonyl-2,5-diazabicyclo- [2,2,2] octane.

Similarly, when benzyl-2,5-diazabicyclo-[2,2,2]octane 5-(4-morpholinocarbonyl -2-carboxylate is similarly treated, the productobtained is 2-(4-morpho1ino-carbonyl)- 2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 30 A mixture of g. of diphenyl-iodonium bromide with g. of2-benZoyl-2,5-diazabicyclo-[2,2,2]octane and 250 ml. of water isrefluxed until the reaction is substantially complete. The reactionmixture is cooled and extracted with ether. The extract is dried oversodium sulfate and yields2-benzoyl-5-phenyl-2,5-diazabicyclo-[2,2,2]octane.

When the above procedure is followed using an equivalent quantity of4-nitro-diphenyl-iodonium bromide, one obtains 2-benzoyl-5-(p-nitrophenyl) -2,5-diazabicyclo- [2, 2,2]octane. When this product isreduced at temperatures between ambient and 50 C. in ethanol solution byhydrogenation over 5% palladium charcoal, there is obtained2-benzoyl-5-(p-aminophenyl)-2,5-diazabicyclo-[2,2, 2]octane.

EXAMPLE 31 Z-phenyl-Z,S-diazabicyclo- [2,2,2 octane The procedure ofExample 25 is followed using an equivalent quantity of the product ofExample 30 in place of the mono-benzoyl compound used in that example.The product thus obtained is 2-phenyl-2,5-diazabicyclo- [2,2,2]octane.

EXAMPLE 32 Benzyl-S-(p-hydroxyphenyl) -2,5-diazabicyclo-[2,2,2]octane-Z-carboxylate The procedure of Example 13 is followed using onemole of benzyl-2,S-diazabicyclo-[2,2,2]octane-2-carboxylate and one moleof 1,4-benzoquinonediazide to yield benzyl-S-(p hydroxyphenyl) 2,5diazabicyclo [2,2,2] octane-2-carboxylate.

When the procedure of Example 29 is followed on this product, oneobtains, by the removal of the carbobenzyloxy group,2-(p-hydroxyphenyl)-2,5-diazabicyclo-[2,2,2] octane.

EXAMPLE 33 Benzyl-S-(p-methoxyphenyl)2,5-diazabicyclo-[2,2,2]

octane-Z-carboxylate A solution of 0.1 mole ofbenzyl-5-(p-hydroxyphenyl)- 2,5-diazabicyclo-[2,2,2]octane-2-carboxylate in 400 ml. of 1 N sodium hydroxide is treated with0.11 mole of dirnethylsulfate with vigorous stirring. After 2 hours, theproduct is extracted with ether, washed with water and dried over sodiumsulfate. Evaporation of the dried solution and purification of theresidue on a column of neutral alumina (500 g.), using a mixture ofether-ethyl acetate as eluent, gives the product,benzyl-5-(p-methoxyphenyl)- 2,5-diazabicyclo- [2,2,2]octane-Z-carboxylate.

When the procedure of Example 29 is followed on the above product, thereis obtained 2-(p-methoxyphenyl)- 2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 34 Benzyl-5-p-acetamidophenyl-2,5-diazabicycl0-[2,2,2]octane-Z-carboxylate The procedure of Example 13 is followed using onemole of benzyl-2,5-diazabicyclo-[2,2,2]octane-2-carboxylate and one moleof acetamidoquinone diazide to producebenzyl-S-p-acetamidophenyl-Z,5-diazabicyclo-[2,2,2]octane-2-carboxylate.

EXAMPLE 35 2-p-aceiamidophenyl-2,5-diazabicycle- [2,2,2] octane Theprocedure of Example 29 is followed on the product of Example 34 toproduce by removing the chlorobenzyloxy group,2-p-acetamidophenyl-2,S-diazabicyclo- [2,2,2] octane.

EXAMPLE 36Z-benzoyl-S-(p-dimethylaminophenyl)-2,5-diazabicycl0-[2,2,2]0ctane Theprocedure of Example 13 is followed using as the starting material the2-benZoyl-5-(p-aminophenyl)-2,5-diazabicyclo-[2,2,2]octane prepared inExample 30.

When this product is used in the procedure of Example 25, there isobtained 2-(p-dimethylaminophenyl)-2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 37 Z-benz0yZ-5-benzyl-2,5-diazabicycl0-[2,2,2]octane Theprocedure of 14B is followed using 2-benzoyl-2,5-

15 diazabicyclo-[2,2,2]octane and benzyl chloride as the reagents toproduce Z-benzoyl-5-benzyl-2,S-diazabicyclo- [2,2,2]octane.

When this product is used in the procedure of Example 25 there isobtained 2-benzyl-2,S-diazabicyclo-[2,2,2]octane.

When this product is used in the procedure of Example 25 there isobtained 2-benzyl-2,S-diazabicyclo-[2,2,2]-octane.

Similarly, when instead of benzyl chloride, there is used'2-benzoyl-2,S-diazabicyclo-[2,2,2]octane and mxylylbromide inequivalent quantities in the procedure of Example 14B, there is obtained2-benZoyl-5-m-xylyl- 2,5-diazabicyclo-[2,2,2]octane. When this productis used in the procedure of Example 25, the resulting product is2-m-xylyl-2,S-diazabicyclo-[2,2,2]octane.

EXAMPLE 38 2-0-methylthiophenyl-2,5-ziiazabicycl0-[2,2,2 octane Amixture of one-tenth mole of the product of Example 1, one-tenth mole ofo-metnylthioaniline, 500 ml. of nitrobenzene, one-tenth mole of copperpowder and 50 g. of sodium carbonate is stirred at 200 C. until reactionis substantially complete. The hot reaction mixture is filtered and thefiltrate is cooled. The filtrate is then concentrated under reducedpressure and the residue is dissolved in alcohol and absorbed on asilica gel column. The product is then eluted from the column withsuccessively increasing portions of ether in ether-petroleum ethermixtures and the fractions are thus separated to yield a small amount ofthe bis-methylthioanilino adipic ester and the monobromo, monomethylthioanilino adipic esters. The mono product thus obtained is thensuccessively put through the procedures of Examples 2, 3, 4, and 5 toyield 2-o-methylthiophenyl-Z,S-diazabicyclo-[2, 2,2]octane.

When the above procedure is used, substituting an equivalent quantity ofo-anisidine for the o-methylthioaniline, there is obtained thecorresponding 2-o-methoxyphenyl-2,5-diazabicyclo [2,2,2]octane.

EXAMPLE 39 EXAMPLE 41 2-meZhyl-5-[oz-(2'-chl0r0-10-phenothiazinyl)-prpyl] 2,5-diazabicyclo-[2,2,2]0ctane The procedure of Example 148 isfollowed using as the reagents 2-methyl-2,S-diazabicyclo-[2,2,2]octaneand N-(3-chloropropyl)-2chloropl1enothiazine to yield 2- methyl 5 [a (2'chloro phenothiazinyl) propyl]-2,5-diazabicyc1o-[2,2,2]octane.

EXAMPLE 42 2-fl-hyriroxyethyl-5-[a-(2'-chl0r0-] 0'-phenothiazinylpropyl] -2,5-diazabicyclo- [2,2,2 1 octane The procedure of Example 14Bis followed using as the reagentZ-fl-hydroxyethyl-Z,S-diazabicyclo-[2,2,2]oc.

tane and N-3-chloropropyl-Z-chlorophenothiazine to yield 2 5hydroxyethyl 5 [or (2' chloro 10" phenothiazinyl -propyl-2,5-diazabicyclo- 2,2,2] octane.

EXAMPLE 43 2-174 ethyl-5 -cyan0metltyl-2 ,5 -di azabicycl0- [2 ,2,2octane The procedure of Example 15 is followed using as the reagent2-methyl-2,5-diazabicyclo-[2,2,2]octane and chloroacetonitrile to yieldZ-methyl-5-cyanomethyl-2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 44 2-methyl-S-fi-amin0ethyl-2,5-diazabicycl0-[2,2,2]0ctane Theprocedure of Example 18 is followed using in place of the bis-methylcompound the Z-methyl derivative present in Example 43 to yieldZ-methyI-S-fl-aminocthyl- 2,5-diazabicyclo-[2,2,2]octane.

EXAMPLE 45 2-hydr0xyethyl-.i-cyanomethy[-2,S-diazabicyclo-[2,2,2] octaneSeventy-five hundredths. ml. of 37% formaldehyde is added to 1.14 gms.sodium bisulfite and the mixture is diluted with Water to a volume of 3ml. This is cooled and added to 1.4 gins. coldZ-fi-hydroethyl-2,5-diazabicycle-[2,2,2]octane. The mixture is. allowedto come to room temperature with stirring. A homogeneous solution formsand then a crystalline solid is precipitated. Potassium cyanide (0.72g.) is dissolved in Water to a total of 2 ml. This is then added to thefirst reaction mixture and the new mixture is heated on the steam bath.It becomes homogeneous at first and then a solid plus an oilprecipitate. The mixture is heated 1 hour and then allowed to standovernight at room temperature. It is then shaken with chloroform and thechloroform layer is removed. The aqueous layer is diluted with somewater, saturated with potassium carbonateand then extracted severaltimes with chloroform. The chloroform extracts are combined, dried andevaporated in vacuo to give 1.7 gins. of crude product. Purification isachieved by adsorption on neutral alumin and elution withchloroform-ether mixtures.

EXAMPLE 46 Z-hydroxyethyl-S-fi-aminoethyl-Z,S-a'iazabicyclo- (2,2,2)

- octane The procedure of Example 18 is followed using the product ofExample 45 in place of the product used therein to yield2-hydroxyethyl-5-,B-aminoethyl-Z,5-diazabicyclo-(2,2,2)octane.

EXAMPLE 47 I 2-methyl-5-[N-(4-methyl-10-thiaxanthonyl-I -2-amz'rto ethyll -Z,5 -diazabicycl0-[2,2,2]0ctane2-0-meth0xypherzyl-5-(3-p-flzt0r0bnzoyl propyl -2,5- diazabicyclo-[2,2,2 octane The procedure of Example 143 is followed using as thereagents 4-chloro-4'-fiuorobutyrophenone and 2-0-methoxyphenyl-Z,S-diazabicyclo- [2,2,2] octane to produce2-o-methoxyphenyl-5-(3-p-fluorobenzoyl propyl) -2,5-diazabicyclo-[2,2,2] octane.

The solution is then concen- 1 7 EXAMPLE 492-o-methoxyplzenyl-5-(4-p-fln0r0phenyl-4-hydroxybutyl) 2,5-diazabicyclo-[2,2,2] octane The product of Example 48 is dissolved in ethanol andhydrogenated over platinum oxide. The catalyst is filtered and thesolution is evaporated to dryness to yield2omethoxyphenyl-S-(4-p-fiuorophenyl-4-hydroxybutyl) 2, 5 -diazabicyclo-[2,2,2] octane.

EXAMPLE 50 2-nitr0s0-5-benz0yl-2,5-diazabicyclo- [2,2,2] octane EXAMPLE51 2-benz0yl-5-aminc-2,5-diazabicyclo- [2,2,2 octane The product ofExample 50 is dissolved in aqueous acetic acid and an excess of zincdust is added in small portions. The mixture is then refluxed untilreduction is substantially complete. The dust is filtered off and theproduct is recovered by evaporation of the solvents under reducedpressure to give 2-benzoyl-5-amino-2,S-diazabicyclo- 2,2,2] octane.

EXAMPLE 52 2benz0yl-5-benzoylamino-2,S-a'iazabicyclo- [2,2,2 octane Theprocedure of Example 7 is followed using 2-benzoyl-S-amino-Z,S-diazabicyclo-[2,2,2]octane and benzoyl chloride indry pyridien as the reagents to produce 2-benzoyl-S-benzoylamino-2,S-diazabicyclo- [2,2,2] octane.

EXAMPLE 5 3 2-benzyl-5-ethylamina-2,5-diazabicyclo- (2,2,2 octane Onepart of 2-benzoyl-5-acetylamino-2,S-diazabicyclo- (2,2,2)octane,suspended in 25 parts of freshly distilled dry tetrahydrofuran, is addedslowly to a stirred suspension of 1 part lithium aluminum hydride in 100parts tetrahydrofuran. After addition is complete, the mixture isrefluxed overnight. It is then cooled and 5 parts water is addeddropwise with stirring. The mixture is allowed to come to roomtemperature over 2 hours, filtered, and the solids washed with ether.The filtrates are combined and taken to dryness in vacuo. (The residueis dissolved in a minimum amount of dry methanol, saturated with dryhydrogen chloride and diluted with excess dry ether. The white solidwhich precipitates is filtered. After standing overnight, theprecipitate is washed with ether and dried in vacuo at roomtemperature.) The residue is chromatographed on 30 parts of neutralalumina using ether-petroleum ether as eluent.

EXAMPLE 54 2-benz0yl-5-benzylamino-2,S-diazabicyclo- (2,2,2)0ctane A. Amixture of 0.1 mole of 2-benzoyl-5-amino-2,5- diazabicyclo(2,2,2)octanein 50 ml. ethanol is treated with 0.1 mole of benzaldehyde. The mixtureis stirred for several hours and the precipitate filtered and washedwith ethanol and dried in a dessicator in vacuo.

The azomethine is hydrogenated in ethyl acetate at room temperature and40 p.s.i. using Raney nickel catalyst. After filtration of the catalystand removal of solvent there is obtained a residue of the desiredcompound of good purity. Further purification may be realized byrecrystallization from benzene-Skellysolve B.

B. The compound may be also obtained by hydrogenation of the mixture ofamine and aldehyde in situ under the same conditions as in Example A.

1% EXAMPLE 5s Z-ethylamin0-2,5-diazabicyclo-(2,2,2 octane A mixture of2-ethyl-5-benzyl-2,S-diazabicyclo-(2,2,2) octane in ethanol iscatalytically reduced using palladium on charcoal at 40 p.s.i. and roomtemperature. The catalyst is filtered, washed with fresh ethanol and thecombined filtrates are taken to dryness in vacuo. The crude residue ispurified by distillation in vacuo.

EXAMPLE 5 6 Z-benzylamin0-2,5-diazabicyclo-(2,2,2)octane A mixture of 1part of Z-benzylarnino-S-benzoyl-2,5- diazabicyclo-(2,:2,2)octane and 20parts 10% sodium hydroxide is refluxed overnight. The mixture is cooled,saturated with potassium carbonate and extracted with chloroform. Thechloroform is dried and taken to dryness in vacuo yielding a residue of2-benzylamino-2,5-diazabicyclo-(2,2,2)octane.

EXAMPLE 5 7 2-phenyl-5- a-tetrahydropyryl) -2,5-diazabicyclo [2 ,2 ,2octane To a solution of 0.1 mole of 2-phenyl-2,S-diazabicyclo-[2,2,2]octane in 60 ml. of methanol is added 11.2 g. (0.11 mole) of2-hydroxytetrahydropyran quickly with cooling and stirring. The reactionmixture is kept at room temperature for two hours and then concentratedin vacuo to about one half of its volume. The concentrate is poured intoWater and extracted With ether. The ether solution is dried overpotassium carbonate and evaporated to a residue. The residue ischromatographed on 1 pound of neutral alumina using ether-petroleumether as the eluent.

The free base (10 g.) is dissolved in 200 ml. hot methanol and mixedwith ml. of isopropanol saturated with hydrogen chloride to give thedihydrochloride.

EXAMPLE 5 8 2 (p-meth oxyphenyl) -5- a-tetrahydropyryl -2,5-diazabicyclo- [2 ,2 ,2 octane When an equivalent amount of2-(p-methoxyphenyl)- 2,5-diazabicyclo-[2,2,2]octane is used in place of2-phenyl-2,5-diazabicyclo-[2,2,2]octane in the procedure of Example 57,there is obtained 2-(p-methOXyphenyD-S-(atetrahydropyryl)-2,5-diazabicyclo-[2,2,2] octane and its dihydrochloride.

EMMPLE 59 2- (5 -ni tro-2-thiaz0lyl -5 -acetyl-2,5 -diazabicyclo-[2,2,2] octane A mixture of 0.1 mole of 2-bromo-5-nitrothiazole and 0.12mole of 2-acetyl-2,S-diazabicyclo-[2, 2,2]octane hydrochloride, 25 g. ofsodium bicarbonate and 200 ml. of ethanol is stirred and heated underreflux for 1 hour. After cooling, the crude solid is filtered, dissolvedin chloroform, washed with water and dried over sodium sulfate. Thechloroform solution is evaporated to a residue, which is thenrecrystallized from aqueous acetic acid or alcohol to yield the product.

EXAMPLE 6O 2-(5-nitr0-2-thiaz0lyl) -2,5-diazabicyclo- [2,2,2]octane Asolution of 10 g. of 2-(5-nitro-2-thiazolyl)-5-acetyl-2,5-diazabicyclo-[2,2,2]octane in 70 ml. water and 20 m1. conc. sulfuricacid is heated under reflux for 1 hour and filtered. The filtrate iscooled in an ice-bath and neutralized with concentrated ammoniumhydroxide to a pH of 8. The solid product separated is filtered, Washedwith water and recrystallized from ethanol.

a 9 EXAMPLE 61 A solution of 0.05 mole of 2-(5-nitro-2-thiazolyl)-2,5-diazabicyclo-[2,2,2]octane, 0.055 mole of diethylcarbamyl chloride and0.1 mole of triethylamine in 200 ml. benzene is heated under reflux for4 hours. The cooled solution is washed with water and dried over sodiumsulfate. After evaporation, the residue is chromatographed on a columnof 800 g. of silica gel using benzene-Skellesolve B as eluent.

EXAMPLE 62 N-substituted-2,5-diazabicycl-[2,2,1] heptanes When theproduct of Example 6 is used in any of the examples, 7 through 58, inequivalent quantities in place of the 2,5-diazabicyclo-[2,2,2]octane,the corresponding 2,5-diazabicyclo-[2,2,1]heptane is obtained.

We claim:

1. A compound of the formula in which R and R are each selected from thegroup consisting of hydrogen; carbocyclic aroyl in which the carbocyclicradical has less than three fused six-membered rings; substitutedcarbocyclic aroyl in which the carbocyclic radical has less than threefused six-membered rings and in which the substituents are selected fromthe group consisting of lower alkoxy and lower alkanoyloxy; loweralkanoyl; substituted lower alkanoyl in which the substituent isselected from the group consisting of halogen and phenyl; cinnamoyl;monocyclic heteroaroyl in which the heterocyclic ring has less than 7and more than 4 atoms, there being no more than two heteroatoms in saidring, the said heteroatoms being selected from the group consisting ofnitrogen, oxygen and sulfur; nitro substituted monocyclic heteroaroyl inwhich the heterocyclic ring has less than 7 and more than 4 atoms, therebeing no more than two heteroatoms in said ring, the said heteroatomsbeing selected from the group consisting of nitrogen and sulfur;carboxy; substituted carboxy of the formula COM in which M is selectedfrom the group consisting of phenoxy, nitrophenoxy, lower alkoxy, di-(lower alkyl) amino and diphenylamino; lower alkyl; substituted loweralkyl in which the substituent is selected from the group consisting ofcarb-lower alkoxy, cyano, hydroxy, amino, lower alkanoylamino di(loweralkyl) amino, benzodioxanyl, phenyl, halophenyl, halobenzoyl,chlorophenothiazinoyl; phenyl; substituted phenyl in which thesubstituent is selected from the group consisting of hydroxy, loweralkanoylamino, amino, di(lower alkyl)amino, lower alkoxy, lower alkyl,lower alkyl mercapto and the group di(lower alkyl) aminophenylsulfonyl;N-morpholinylsulfonyl; N-pyrrolidinyl sulfonyl; phenylthio; lower alkylsubstituted phenylthio; nitroso; amino; substituted amino in which thesubstituent is selected from the group consisting of benzoyl, loweralkyl and benzyl; pyranyl; thiazolyl; and nitrothiazolyl; and R is analkylene bridge of less than three carbons.

2. 2,5-diazabicyclo-[2,2,2]octane.

3 2,5 -diazabicyclo- [2,2, 1 1 heptane.

,l 2% 4. A compound of the formula 0 E R1N R3 NR OH-C II in which R andR are each selected from the group consisting of hydrogen; canbocyclicaroyl in which the carbocyclic radical has less than three fusedsix-membered rings; substituted carbocyclic aroyl in which thecarbocyclic radical has less than three fused six-membered rings and inwhich the substitutents are selected from the group consisting of loweralkoxy and lower alkanoy-loxy; lower alkanoyl; substituted loweralkanoyl in which the substituent is selected from the group consistingof halogen and phenyl; cinnamoyl; monocyclic heteroaroyl in which theheterocyclic ring has less than 7 and more than 4 atoms, there being nomore than two heteroatorns in said ring, the said heteroatoms beingselected from the group consisting of nitrogen, oxygen and sulfur; nitrosubstituted monocyclic heteroaroyl in which the heterocyclic ring hasless than 7 and more than 4 atoms, there being no more than twoheteroatoms in said ring, the said heteroatoms being selected from thegroup consisting of nitrogen and sulfur; carboxy; substituted carboxy ofthe formula COM in which M is selected from the group consisting ofphenoxy, nitrophenoxy, lower alkoxy, di(lower alkyl) amino anddiphenylamino; lower alkyl; substituted lower alkyl in which thesubstituent is selected from the group consisting of carb-lower alkoxy,cyano, hydroxy, amino, lower alkanoylamino di(lower alkyl) amino,benzodioxanyl, phenyl, halophenyl, halobenzoyl, chlorophenothiazinoyl;phenyl; substituted phenyl in which the substituent is selected from thegroup consisting of hydroxy, lower alkanoylamino, amino, di- (loweralkyl)amino, lower alkoxy, lower alkyl, lower alkyl mercapto and thegroup di(lower alkyl) aminophenylsulfonyl; N-morpholinylsulfonyl;N-pyrrolidinyl sulfonyl; phenylthio; lower alkyl substituted phenylthio;nitroso; amino; substituted amino in which the substituent is selectedfrom the groupconsisting of benzoyl, lower alkyl and benzyl; pyranyl;thiazolyl; and nitrothiazolyl; and R is an alkylene bridge of less thanthree carbons.

5. The compound H-N CED-GENE 6. The compound 7. A compound of theformula OHOH2 in which R and R are each selected from the groupconsisting of hydrogen; carbocylic aroyl in which the carbocyclicradical has less than three fused six-membered rings; substitutedcarbocyclic aroyl in which the carbocyclic radical has less than threefused siX-membered rings and in which the substitutents are selectedfrom the group consisting of lower alkoxy and lower alkanoyloxy; loweralkanoyl; substituted lower alkanoyl in which the substituent -isselected from the group consisting of halogen and phenyl; einnamoyl;monocyclic heteroaroyl in which the heterocyclic ring has less than 7and more than 4 atoms, there being no more than two heteroatoms in saidring, the said heteroatoms being selected from the group consisting ofnitrogen, oxygen and sulfur; nitro substituted monocyclic heteroaroyl inwhich the heterocyclic ring has less than 7 and more than 4 atoms, therebeing no more than two heteroatoms in said ring, the said heteroatomsbeing selected from the group consisting of nitrogen and sulfur;carboxy; substituted carboxy of the formula COM in which M is selectedfrom the group consisting of phenoxy, nitrophenoxy, lower alkoxy,di(lower alkyl) amino and diphenylamino; lower alkyl; substituted loweralkyl in which the substituent is selected from the group consisting ofcarb-lowcr alkoxy, cyano, hydroxy, amino, lower alkanoylamino di(loweralkyl) amino, benzodioxanyl, phenyl, halophenyl, halobenzoyl,chlorophenothiazinoyl; phenyl; substituted phenyl in which thesubstituent is selected from the group consisting of hydroxy, loweralkanoylamino, amino, di- (lower alkyl) amino, lower alkoxy, loweralkyl, lower alkyl mercapto and the group References Cited in the fileof this patent UNITED STATES PATENTS 2,744,086 Mowry et a1. May 1, 19562,832,784 Har-fenist et a1 Apr. 29, 1958 2,872,476 Melkonian et a1 Feb.3, 1959 2,905,706 Sims et a1 Sept. 22, 1959 3,068,233 Moss Dec. 11, 1962OTHER REFERENCES Barnes et al.:Journal American Chemical Society, vol.75, pp. 975-977 (1953).

Blackman et al.: Journal Organic Chemistry, vol. 26, pp. 2750-2755(1961).

1. A COMPOUND OF THE FORMULA
 7. A COMPOUND OF THE FORMULA 